3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride | 113942-58-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑四嗪类
• 英文名称: 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride
• 英文别名: 3,4-dihydro-3-methyl-4-oxo-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carbonyl chloride；3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride
• CAS: 113942-58-8
• 化学式: C₆H₄ClN₅O₂
• 分子量: 213.583
• InChiKey: BSUDWRFSPBCMQL-UHFFFAOYSA-N

物化性质

• 熔点：
  142-143 °C
• 沸点：
  398.3±34.0 °C(Predicted)
• 密度：
  1.92±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  79.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride 在 palladium 10% on activated carbon 氢气 作用下， 以 四氢呋喃 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 73.5h， 生成 N-hydroxy-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
  参考文献：
  名称：

  [EN] 3-SUBSTITUTED-8-SUBSTITUTED-3H IMIDAZO[5,1-D][1,2,3,5-TETRAZIN-4-ONE COMPOUNDS AND THEIR USE
  [FR] COMPOSÉS 3H-IMIDAZO[5,1-D][1,2,3,5-TÉTRAZIN-4-ONE 3-SUBSTITUÉS-8-SUBSTITUÉS ET LEUR UTILISATION

  摘要：

  本发明一般涉及治疗化合物领域，更具体地涉及以下公式的3-取代-8-取代-3H-咪唑[5,1-d][1,2,3,5]四唑-4-酮化合物，其中-A和-B如本文所定义（统称为38TM化合物）：（1）。本发明还涉及包含这种化合物的药物组合物，以及利用这种化合物和组合物在体外和体内抑制细胞增殖，治疗增生性疾病如癌症等的用途，以及制备这种化合物的方法。

  公开号：

  WO2010149968A1
• 作为产物：
  描述：

  替莫唑胺 在 氯化亚砜 、 硫酸 、 N,N-二甲基甲酰胺 、 sodium nitrite 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 19.0h， 生成 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride
  参考文献：
  名称：

  A novel series of phenolic temozolomide (TMZ) esters with 4 to 5-fold increased potency, compared to TMZ, against glioma cells irrespective of MGMT expression

  摘要：

  诊断为多形性胶质母细胞瘤（GBM）的患者的标准治疗是替莫唑胺（TMZ）。

  DOI：

  10.1039/d0ra02686g

文献信息

• Synthesis and Antitumor Activity of 3-Methyl-4-oxo-3,4-dihydroimidazo [5,1-d][1,2,3,5]tetrazine-8-carboxylates and -carboxamides
  作者：Dan Liu、Jian-Guo Yang、Jie Cheng、Lin-Xiang Zhao

  DOI：10.3390/molecules15129427

  日期：——

  Seventeen novel 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate and -carboxamide derivatives were synthesized and evaluated for their growth inhibition in seven human solid tumor and a human leukemia HL-60 cell lines. Compound IVa showed more activity than the other compounds and the positive control temozolomide. In the presence of 40 mg/mL of IVa, the survival rate of all tested tumor cells was less than 10%. Esters displayed more potent antitumour activity than amides and temozolomide against HL-60 cells. These compounds also exhibited considerably enhanced water-solubility.

  合成了17种新颖的3-甲基-4-氧代-3,4-二氢咪唑并[5,1-d][1,2,3,5]四氮杂-8-甲酸酯和甲酰胺衍生物，并评估了它们对7种人实体瘤和一种人白血病HL-60细胞系的生长抑制作用。化合物IVa显示出比其他化合物和阳性对照替莫唑胺更高的活性。在IVa浓度为40 mg/mL时，所有检测的肿瘤细胞存活率均低于10%。酯类化合物对HL-60细胞的抗肿瘤活性比酰胺类和替莫唑胺更强。这些化合物还表现出显著增强的水溶性。
• 테모졸로마이드와 NPPB(5-니트로-2-(3-페닐프로필아미노)벤조산)를 결합한 화합물 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY 한국과학기술연구원(319980077518) BRN ▼209-82-03522

  公开号：KR20160052012A

  公开（公告）日：2016-05-12

  본 발명은 뇌종양 치료제인 테모졸로마이드(temozolomide, TMZ)를 클로라이드 채널 저해제인 5-니트로-2-(3-페닐프로필아미노)벤조산 (5-nitro-2(3-phenylpropylamino)-benzoic acid, NPPB)를 결합한 화합물(이하, TMZ-NPPB로 약칭한다.) 또는 이의 약제학적으로 허용 가능한 염, 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물에 관한 것이다. 본 발명에 따른 화합물은 암 세포에 대한 세포사멸 활성과 세포침습 저해활성을 동시에 가짐으로써 뛰어난 항암활성을 나타내는바, 악성 신경교아종, 흑색종, 아교모세포종 및 기타 뇌암, 식도암, 췌장암, 폐암, 침윤성 직장암, 유방암, 전이성 전립선암, 난소암 등과 같은 다양한 암의 예방 및 치료에 유용하게 사용될 수 있다.

  This invention relates to a compound of temozolomide (TMZ), a brain tumor therapeutic agent, combined with 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), a chloride channel blocker (hereinafter referred to as TMZ-NPPB) or a pharmaceutically acceptable salt thereof, contained in a pharmaceutical composition for the prevention or treatment of cancer. The compound according to the invention exhibits excellent anti-cancer activity by simultaneously possessing cytotoxic activity against cancer cells and inhibitory activity against cell invasion, and can be effectively used for the prevention and treatment of various cancers such as malignant gliomas, melanomas, neuroblastomas, and other brain tumors, esophageal cancer, pancreatic cancer, lung cancer, invasive colorectal cancer, breast cancer, metastatic prostate cancer, ovarian cancer, etc.
• PROCESS FOR THE COVALENT COUPLING OF TWO MOLECULES BY MEANS OF A DIELS-ALDER REACTION WITH INVERSE ELECTRON REQUIREMENT
  申请人：Wiessler Manfred

  公开号：US20100016545A1

  公开（公告）日：2010-01-21

  The present invention relates to a process for linking two molecules by means of a Diels Alder reaction with inverse electron requirement (DARinv), comprising the following steps: reaction of a (a) triazine or tetrazine with one or more electron-attracting substituents on the ring as a diene component, the electron-attracting substituents being selected from: COOR C(O)NR 2 CX 3 (X=halogen) halogen CN SO 2 —R or SO 3 —R PR 2 wherein R═H, alkyl, aryl, heterocycle, which in turn may be substituted, where appropriate, with alkyl, OH, SH, halogen, aryl, heterocycle, nitro, carboxyamido or amine group. —heterocyclic rings having 1, 2 or 3 N, O or S atoms with a ring size of 5 or 6 ring members, which are substituted with at least one carboxyl, sulfonic acid or phosphone group with (b) an isolated double bond or triple bond in a (hetero)carbocyclic ring or an isolated olefinic double bond or triple bond in a linear or branched hydrocarbon chain which may also contain heteroatoms, where appropriate, as a dienophile component.

  本发明涉及一种利用逆电子需求的Diels-Alder反应（DARinv）将两种分子通过连接的方法，包括以下步骤：将（a）三嗪或四嗪与环上的一个或多个吸电子取代基反应作为二烯组分，所述吸电子取代基被选择自：COOR、C（O）NR2、CX3（X=卤）、卤、CNSO2—R或SO3—RPR2，其中R=H、烷基、芳基、杂环，后者可能被适当地取代，如有必要，可用烷基、OH、SH、卤、芳基、杂环、硝基、羧基氨基或胺基团取代；（b）一种孤立的双键或三键存在于（杂）碳环上，或者一种孤立的烯烃双键或三键存在于线性或支链烃链中，该链也可能含有杂原子，如有必要，作为二烯酰组分。
• Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma
  作者：Riley L. Svec、Lucia Furiassi、Christine G. Skibinski、Timothy M. Fan、Gregory J. Riggins、Paul J. Hergenrother

  DOI：10.1021/acschembio.8b00864

  日期：2018.11.16

  (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel

  即使在个性化医学和免疫疗法的时代，替莫唑胺（TMZ），一种小分子DNA烷基化剂，仍然是胶质母细胞瘤（GBM）的护理标准。TMZ具有异常的作用方式，可通过体内水解自发转化为其活性成分。尽管TMZ已获得FDA批准长达20年之久，但对于肿瘤表达抗性酶MGMT并通过骨髓抑制引起全身毒性的患者，TMZ几乎没有益处。TMZ于1984年首次合成，但由于TMZ的化学敏感性，无法获得某些关键衍生物，这排除了对咪唑四嗪结构与生物活性之间联系的广泛探索。在这里，我们试图辨别咪唑并四嗪的水解稳定性和抗癌活性之间的关系，目的是确定前药激活的最佳时机，并通过增加血脑屏障的渗透性来开发具有增强功效的合适化合物。这项工作需要开发新的合成方法，以便在咪唑并四嗪的C8位上获得以前未开发的功能（例如脂族，酮，卤素和芳基）。通过合成和评估一系列具有一定范围水稳定性（0.5至40 h）的化合物，我们基于C8取代基的Hammett常
• [EN] IMIDAZOTETRAZINE COMPOUNDS<br/>[FR] COMPOSÉS D'IMIDAZOTÉTRAZINE
  申请人：UNIV ILLINOIS

  公开号：WO2020033880A1

  公开（公告）日：2020-02-13

  New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

  新的合成方法提供了对咪唑四唑的C8位置以前未探索功能的访问。通过合成和评估一系列具有不同水稳定性（从0.5到40小时）的化合物，基于C8取代基的Hammett常数建立了咪唑四唑水解稳定性的预测模型。鉴定了具有活性的化合物，对一系列GBM细胞系具有活性，具有适当的水解和代谢稳定性，并且脑血清比例相对于TMZ显著升高，导致较低的血液毒性剖面和在GBM小鼠模型中优于TMZ的活性。